1. Resting-state activity and behavioral performance: Although resting-state brain activity has been shown to correspond with task-evoked brain activation, the relationship between intrinsic and evoked parametric activity has not been elucidated. We studied HC subjects with resting-state and N-back working memory (WM) task. Using amplitude of low-frequency fluctuation (ALFF) as an index of intrinsic resting-state activity (RSA), we found that ALFF in the middle frontal gyrus and inferior/superior parietal lobules was positively correlated with WM task-evoked activation, while ALFF in the medial prefrontal cortex, posterior cingulate cortex, superior frontal gyrus, superior temporal gyrus, and fusiform gyrus was negatively correlated with WM task-evoked deactivation. The relationship between intrinsic RSA and task evoked activation in lateral/superior frontal gyri, inferior/superior parietal lobules, superior temporal gyrus, and midline regions were stronger at higher WM task loads. Also, both RSA and task-evoked activation in the superior parietal lobule/precuneus were significantly correlated with WM task behavioral performance, explaining intersubject performance variance. These data suggest intrinsic RSA facilitates or is permissive of specific brain circuit engagement to perform a cognitive task and that it can predict subsequent task-evoked brain responses and behavioral performance. 2. Resting state network dynamics: A major challenge in treating cocaine addiction is identifying factors to predict recidivism. Abstinence from cocaine may alter connectivity within and between 3 resting state networks (RSN), the default mode network (DMN), executive control network (ECN) and the salience network (SN). Changes in RSN dynamics may be driven by and contribute to symptom severity during cocaine abstinence, and thus may prove more sensitive to underlying abstinence-related processes than self-report or neurocognitive measures. We investigated whether RSN dynamics measured following a treatment episode could predict relapse. Group-level independent component analysis identified DMN, ECN and SN from resting BOLD data. Enhanced connectivity between right and left ECN was associated with significantly reduced risk of relapse by day 30 and time to relapse 24wks post-treatment. Increased relapse risk was associated with enhanced connectivity within the DMN. Relapse was unrelated to the neurocognitive and clinical measures. Findings are consistent with evidence of enhanced DMN engagement as a function of drug craving and cognitive deficits. They also suggest that interventions to enhance ECN connectivity, a marker of cognitive control, may improve treatment outcomes. Findings highlight the potential utility of resting connectivity measures as a probe of treatment efficacy and relapse risk. 3. Resting Regional Cerebral Blood: Individuals addicted to cocaine exhibit reduced activity and blood flow in the orbitofrontal cortex (OFC) and poor performance on tasks sensitive to OFC functioning. OFC-related dysfunction may contribute to decision making deficits characterizing cocaine addiction and relapse risk. We investigated whether resting regional cerebral blood flow (rCBF) measured following a treatment episode could predict relapse to cocaine use. Pseudo-continuous spin labeling (pCASL) was used to measure rCBF. Relapse by day 30 was associated with reduced rCBF in the left and right medial OFC and enhanced rCBF in the parahippocampal gyrus. Enhanced rCBF in the parahippocampal gyrus also predicted relapse up to 24wks post-treatment. Clinical measures, such as cocaine use history, were unrelated to relapse risk. Relapse by day 30 was associated with perseverative responding and slowed stop signal reaction time relative to controls. Findings indicate that OFC related dysfunction in cocaine-users may predict early relapse following short-term treatment. 4. High risk behavior and MDMA: MDMA (ecstasy), a stimulant and psychedelic, increases serotonin activity in the brain and is linked to high-risk behaviors. It has been shown to modify decision-making and risky behaviors. Drug users and non-users completed the Rogers decision-making task in 3 concurrent fMRI sessions. The MDMA users received 1 of 3 doses of MDMA; control groups received no drug. Preliminary analyses revealed no effect of MDMA administration on MDMA users in the context of the task. However, MDMA users differed significantly from non-drug users on several behavioral task-measures, and activated the posterior cingulate cortex, a region previously implicated in risky decision-making, during risky trials. These results suggest that the high risk behavior seen with MDMA use is either a consequence of chronic MDMA use, or is a pre-existing trait in individuals who use MDMA. 5. Reinforcement learning: We examined the effect of the commonly occurring functional single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1 A118G) on implicit reward learning using a probabilistic signal detection task to determine whether it impacts response bias to monetary reward, in healthy adult subjects: 51 AA homozygotes and 12 G allele carriers. OPRM1 AA homozygotes showed typical, increases in their bias to the rewarded stimulus over time. However, OPRM1 G allele carriers exhibited a decline in response to the rewarded stimulus. These results extend previous reports on the heritability of performance on this task by implicating a specific polymorphism. We suggest a possible mechanism by which the OPRM1 polymorphism may confer reduced response to natural reward through a dopamine-mediated decrease during positive reinforcement learning. 6. Prefrontal white matter (WM) impairment in substance users depends upon the catechol-o-methyl transferase (COMT) val158met polymorphism. Prefrontal WM structure is affected by both extracellular prefrontal dopamine (DA) and by drug addiction. Prefrontal DA modulates descending cortico-striatal glutamatergic pathways that in turn, regulate striatal DA release. The COMT gene contains an evolutionarily recent and common functional variant at codon 108/158 (rs4680) that plays an important role in modulating prefrontal DA tone. Individuals addicted to most substances present with hypoactive DA systems as well as altered WM. Substance users and non-users underwent genotyping and MRI to determine if COMT val158met genotype influences WM integrity fractional anisotropy (FA). A significant Genotype x Drug Use status interaction was found uniquely in the left prefrontal cortex. Post-hoc analysis showed reduced prefrontal FA only in Met/Met homozygotes who were drug users. These data suggest that the Met/Met homozygotes have increased susceptibility to WM structural alterations, which may contribute to the structural and functional prefrontal cortical deficits seen in addiction.